Marion J. G. Bussemakers

Complex cadherin expression in human prostate cancer cells

Changes in cell‐cell interactions are critical in the process of cancer progression. Likewise, it has been shown that loss of expression of the cell adhesion molecule E‐cadherin is associated with grade, stage, and prognosis in many carcinomas, including prostate cancer. Impaired E‐cadherin‐mediated interactions result in an invasive phenotype; however, the mere loss of cell‐cell contact and communication is not the sole explanation for the observed correlation between loss of E‐cadherin‐mediated adhesion and poor clinical outcome. Using a degenerate cloning strategy for sequences that are highly conserved between the various cadherins, we found several other cadherins (N‐ and P‐cadherin and cadherin‐4, ‐6, and ‐11) to be expressed in human prostate cancer cells. Our data suggest that besides loss of E‐cadherin function, also (upregulation of) expression of other cadherins is involved in the acquisition of an invasive and/or metastatic phenotype. Especially, changes in the expression of N‐cadherin and cadherin‐11 may play an important role in prostate cancer progression. Int. J. Cancer 85:446–450, 2000. ©2000 Wiley‐Liss, Inc.

Molecular analysis of multifocal prostate cancer lesions.

To analyse the origin of multifocal prostate cancer lesions, radical prostatectomy specimens from 17 patients were examined. As a marker of genetic lineage, the allelotype based on 33 microsatellite loci was compared between the different tumours present in a given case. Some results provide evidence suggestive of a clonal origin of multiple tumours in a subset of the prostates. In five cases, for example, comparison of multifocal tumour lesions within a given case revealed at least two concordant changes in allelic imbalance (AI) sequence dosages at different loci. In addition, considerable heterogeneity of allelotype was found within and among tumour foci of a given case. In five of the six tumours analysed for intratumour heterogeneity, for example, more than five discordant AI changes were found in one tumour region but not in the other. Conclusions regarding the clonality of such heterogeneous lesions are difficult to draw. A high frequency of AI changes in four lesions exhibiting prostatic intraepithelial neoplasia (mean 6·5 changes per lesion, range 3–6) was found, compared with eight primary tumours present in the same cases (mean 5·8 changes per lesion, range 3–6). The interpretation of AI associated with clinically detected prostate cancer remains a highly complex issue. The fact that no clear evidence was obtained for either a clonal or a non‐clonal origin of multiple lesions in a given prostate indicates that several different mechanisms are likely to operate in establishing the allelotype and that additional evidence from unique mutations or selective gene inactivation may be necessary to obtain definitive results. Copyright

Genetic alterations in prostate cancer.

A number of genetic changes have been documented in prostate cancer, ranging from allelic loss to point mutations and changes in DNA methylation patterns (summarized in Fig. 1). To date, the most consistent changes are those of allelic loss events, with the majority of tumors examined showing loss of alleles from at least one chromosomal arm. The short arm of chromosome 8, followed by the long arm of chromosome 16, appear to be the most frequent regions of loss, suggesting the presence of novel tumor suppressor genes. Deletions of one copy of the Rb and p53 genes are less frequent, as are mutations of the p53 gene, and accumulating evidence suggests the presence of an additional tumor suppressor gene on chromosome 17p, which is frequently inactivated in prostate cancer. Alterations in the E-cadherin/alpha-catenin-mediated cell-cell adhesion mechanism appear to be present in almost half of all prostate cancers and may be critical to the acquisition of metastatic potential of aggressive prostate cancers. Finally, altered DNA methylation patterns have been found in the majority of prostate cancers examined, suggesting widespread alterations in methylation-modulated gene expression. The presence of multiple changes in these tumors is consistent with the multistep nature of the transformation process. Finally, efforts to identify prostate cancer susceptibility loci are under way and may elucidate critical early events in prostatic carcinogenesis.

Molecular genetics and chromosomal alterations in prostate cancer

The multistep nature of carcinogenesis has been repeatedly demonstrated for a variety of human cancers. Concomitant mutational activation of genes that promote cellular growth (i.e., oncogenes) and inactivation of genes that normally act to restrict or otherwise regulate growth (i.e., tumor suppressor genes) are key steps leading to tumor formation. Alterations in such genes can be restricted to the site of the cancer or can be inherited, predisposing a fraction of individuals to develop certain cancers. Evidence has been by the authors and others that chromosomes 8, 10, and 16 harbor potentially novel tumor suppressor genes that are frequently altered in prostatic carcinogenesis. Deletion mapping experiments suggest that critical genes lie on the short arm of chromosome 8 (8p22) and on the long arm of chromosome 16 (16qter‐16q22). A gene in this latter area that we believe plays a critical role in determining the aggressiveness of prostate cancer is the gene for the cell‐cell adhesion molecule, E‐cadherin. Alterations of the expression of this protein or its accessory proteins, the catenins, are found in approximately one‐half of clinically localized tumors and at a higher frequency in tumors that have metastasized (or are likely to). Experimental restoration of the E‐cadherin pathway in prostate cancer cell lines results in suppression of the malignant phenotype. The authors anticipate that understanding the mechanisms by which this and other growth regulatory pathways become altered in prostate cancer will lead to better diagnostic and prognostic markers for this common disease and will possibly identify new approaches for novel therapeutic strategies. Cancer 1995;75:2004–12.

Differential Hybridization Analysis as a Tool to Study Prostatic Cancer Metastasis

The progression of prostate cancer can be described in terms of growth rate, hormone responsiveness, histology and metastatic ability. Some of these parameters can be interdependent. Clearly, metastatic ability of tumor cells is clinically most significant. It is this process in which primary tumor cells spread through the body and grow out at secondary sites that leads to much of lethality due to cancer. For prostate cancer the clinical consequences of established metastatic disease are profound, since no curative therapy is available (1). Systemic palliative methods, based on androgen ablation, are usually succesful, but of limited duration. The outgrowth of androgen insensitive cells is inevitable, and will eventually result in the patients death (2).